The present invention relates to improvements in optical systems and their uses for the measurement of concentration and temperature in scattering media, and the related discrimination of subsurface features. More particularly, the invention provides methods and apparatus which minimize the ratio of diffusely scattered radiation to directly transmitted radiation reaching the detector(s) in optical concentration measurement and imaging apparatus. The methods and apparatus of the invention have special applicability to non-invasive testing, particularly for concentration measurements of materials such as glucose and hemoglobin in blood.
Recent literature is replete with articles describing attempts at performing non-invasive testing using optical measurements (e.g., infrared systems). Part of this expansion has been fueled by the spread of acquired immunodeficiency disease syndrome (AIDS), and the associated fear among public and health care personnel of AIDS. AIDS and other diseases such as hepatitis are born in the blood and can be spread by improper practice of invasive procedures. In addition, the diabetic population has also been anxiously awaiting non-invasive test instruments for many years. Many diabetics must test their blood glucose levels four or more time a day. The modern battery powered instruments for home use require a finger prick to obtain the sample. The extracted blood samples are placed on a chemically-treated carrier which is inserted into the instrument to obtain a glucose reading. This finger prick is painful and can be objectionable when required frequently. In addition, although the price has dropped considerably on these instruments, the cost for the disposable and the discomfort and health risk associated with having open bleeding is undesirable.
Accordingly, a number of groups have recently tried to make non-invasive instruments for testing a variety of analytes, particularly glucose. A recent trend in non-invasive testing has been to explore the use of the near infrared spectral region, primarily 700-1100 nm because this is the spectral response range of the silicon detectors typically used in the prior art. A wider wavelength range to .about.1800 nm can be accessed by the addition of germanium and/or InGaAs detectors, and useful measurements can be made into the 2500 nm range with InSb or other detectors. The region below .about.1400 nm is the most useful in transmission, as tissue is transparent enough there to allow high enough photon flux for accurate detection. Above 1400 nm, the strong absorption of water limits the penetration depth of tissue, so that useful measurements are typically made in reflectance geometry. Below 1100 nm, the penetration of the light is sufficient that the signal modulation during the arterial pulse can be measured comfortably in both transmission and reflectance geometries. Above 1400 nm, such pulsatile measurements are extremely difficult in transmission due to low intensity, and similarly difficult in reflectance because the light does not penetrate deeply enough to sample the pulsatile capillary beds.
Most of the non-invasive testing work has been carried out using classic spectrophotometric methods, such as a set of narrow wavelengths sources, or scanning spectrophotometers which scan wavelength by wavelength across a broad spectrum. The data obtained from these methods are spectra which then require substantial data processing to eliminate background; accordingly, the papers are replete with data analysis techniques utilized to glean the pertinent information. Examples of this type of testing includes the work by Clarke, see U.S. Pat. No. 5,054, 487; and primarily the work by Rosenthal et al., see e.g., U.S. Pat. No. 5,028,787. Although the Clarke work uses reflectance spectra and the Rosenthal work uses primarily transmission spectra, both rely on obtaining near infrared spectrophotometric data.
The major successful application of noninvasive testing is the measurement of hemoglobin oxygen saturation with pulse oximetry. The most common method compares the percentage modulation of the intensity of light traversing a body part at two wavelengths chosen so that the ratio of their respective modulations is a relatively strong function of oxygen saturation. The observed change in this ratio is relatively large because the two hemoglobin species involved have both high enough concentrations and specific absorptions that they dominate the creation of the pulsatile signal components at the wavelengths of interest. As a result, the ratio of modulations can be attributed substantially to the two hemoglobins alone, and only needs to be measured to the order of 0.1% in order to achieve clinically significant detection limits with acceptable universality of calibration.
The optical system in typical pulse oximeters have two or more LED emitters placed side-by-side on one side of a finger, and a single detector receiving the radiation on the other side of the finger. Some more recent systems have the detector on the same side of the tissue as the emitters, with baffles preventing the direct illumination of the detector by the sources. As the sources are physically small and optically displaced from each other and the detector, the light from each detector enters the tissue at slightly different locations, and therefore travel different paths through tissue to the detector.
Despite its relatively large signal levels, pulse oximetry has well-known difficulties such as the selection of an adequately vascular sampling site on each individual and variability of the results with motion of the site and breathing by the patient, as well as sensitivity to changes in blood pressure, heart rate, temperature, and tissue hydration. Disturbances such as motion and breathing artifacts typically appear as statistical outriders, i.e., as measurements which fall well off the "average" calibration curve of the instrument obtained from a group of individuals breathing controlled gas mixtures to vary their oxygen saturation.
The calibration of a pulse oximeter is subject to these same error sources; it is not uncommon to find site-to-site variations on the same individual, with results that suggest that the calibration curve even varies, for example, with the absolute magnitude of the pulsatile signal modulation. The effort to obtain a meaningful universal calibration is clearly at odds with intra- and inter-individual physiological variations.
Despite recent efforts to improve the measurement S/N by increasing source intensities and lowering detector noise, as well as increasing the number of detectors, the frequency of outriders and the universality of calibration have not improved substantially. Thus it is clear that while the light traversing the tissue is being measured more precisely, the site- and physiologically-induced variability has not been improved significantly below the 0.1% level needed for the measurement of oxygen saturation.
While these physical and physiological interferences are marginally acceptable for oxygen saturation measurements, they set a lower limit of detectivity that is too high for other clinical analytes such as glucose and cholesterol for which the combination of concentration and specific absorption requires optical measurements to be made 100-1000 times more precise than for the hemoglobins used in pulse oximetry. The hemoglobins, which in themselves are difficult to calibrate in the presence of these site- and physiologically specific limitations comprise a major background interference for the measurement of such trace constituents as glucose.
The optical systems employed for these lower concentration analytes naturally drew on the experience of pulse oximetry, and typically employ similar arrangements of a plurality of slightly displaced LED's to extend the wavelengths sampled, or which use fiber optics to carry light to and from the sources and/or spectrometers which perform the separation of the signal into the different wavelengths employed. Displacement of the sources and wide numerical apertures for the light entering and leaving the tissue enhance the likelihood that different detected wavelengths will have sampled different portions of the medium. Many of the physiological interferences to accurate measurement are mediated by differences in the mean paths traced by light of different wavelength in traversing the intervening tissue between light source[s] and detector[s]. These path variations are produced, in part, by light scattering in the tissue, which varies with the wavelength of the light and which makes photons follow a jagged overall path from scattering to scattering. The detected signals are a complicated function of both the scattering and the total absorption of all constituents along the longer total path of the light. Thus, the present optical systems used for noninvasive measurement allow and perhaps even encourage light of different wavelengths to travel different paths through the tissue, sampling lateral and axial tissue inhomogeneities differently.
This situation violates a fundamental premise of all optical non-invasive measurement methods; namely, that the light intensity which is measured in the individual detection channels can be attributed to the analyte and not to any difference in tissue sampling. Tissue inhomogeneity produces wavelength-dependent spreading of the light which ultimately reaches the detectors, and in the extreme of high scattering and large inhomogeneity, the mixture of detector signals becomes an uncontrollable and uncalibratable average response to the physiological and biochemical conditions at the sampled site.
In addition the existing noninvasive art has employed spectrophotometric methods which limit the intensity of light detected in the individual resolution elements, and which also apply the method in a way which uses the available spectral information inefficiently. These methods were conceived primarily for accurate determination of narrow band spectral structures rather than for discriminating the presence of weak broadband features in strong broadband backgrounds that characterize the noninvasive measurement problem for constituents such as glucose. The multivariate analysis mathematics required to separate the analyte signature from strongly overlapping interferent signatures also introduces an error propagation penalty that compounds the intensity limitation by increasing the impact of detector noise on the calculated measure of concentration.
Improvements that enhance the solution of problems of interference in broadband spectra, by obtaining different raw data, are described in U.S. Pat. No. 5,321,265 (the "Block '265 patent"). This patent sets forth a different approach in non-invasive testing as compared with the prior instruments and methods. As noted, substantially all workers in the non-invasive testing field prior to the Block '265 patent were using classic spectrophotometric instrumentation and substantial processing in an attempt to resolve the low resolution features from the background. However, the spectra of analytes such as glucose in a human body are not discrete high resolution features which spectrophotometric instruments were originally designed to measure but rather have a few low resolutions features with much of the information contained in subtle variations of the detected intensity as a function of wavelength. As such, these spectra appear more like reflectance spectra of colored objects in the visible region. The Block '265 patent teaches the use of an analog of human color perception to obtain meaningful data by means of methods and apparatus which utilize overlapping, broadbeam detectors to mimic the spectral response characteristics of the human retinal cones, but translated into the near-infrared. This approach, which is radically different than classic spectrophotometric measurements, provides advantageous effects in determining the concentration of glucose and other similar materials in an aqueous solution and is particularly advantageous for use with scattering media such as tissue where it also provide the added advantage of higher light flux at the detectors so that the intrinsic shot-noise limitation as a percentage of the total signal intensities is reduced.
U.S. patent applications Ser. Nos. 08/130,257, 08/182,572 and 08/333,758, the disclosures of which are incorporated herein by reference, all disclose improvements in the basic techniques and apparatus described in the Block '265 patent. These improvements include the concepts of congruent illumination and detection of light emerging from the sampled tissue site, pulsatile processing, modulation of illumination sources as a means of eliminating unwanted radiation, the use of non-overlapping broad beam radiation as well as overlapping radiation, and a number of variations thereon. These applications make it clear, in part, that a variety of techniques are useful (and in some instances may be necessary) to deal with the problems encountered in non-invasive measurement of analyte concentration in tissue or other scattering media. Many of these problems arise from the fact that scattering media exhibit higher effective path lengths than their physical dimensions because of scattering by the samples themselves. In fact, the samples, such as human tissue, act as if they are formed of a plurality of scattering sites or centers in the sample. Techniques such as the congruent illumination and congruent detection described in these patent applications equalize the acceptance angles and distances traveled by light of different wavelengths outside the scattering media. Technically, this is achieved by locating all the illumination sources and/or detectors so that the path lengths and angles between the media and the detector(s)/source(s) are equal, so that the detectors or radiation sources act as if they were optically superimposed.
However, the desired congruency of detected light is degraded within the observed media because the multiple scatterings of light spread the light beam to adjacent regions in a way which is strongly wavelength dependent. If the scattering media is inhomogeneous, the result of this spreading is to mix light from these adjacent structures in relative amounts which are dependent on wavelength. One object of the present invention is to reduce this disturbing effect by refining the launch and detection optics to limit their angular acceptance ranges.
It has long been known that a certain portion of the illuminating radiation survives transit across a turbid sample without being either scattered or absorbed, while a much larger portion is scattered in all directions. The more scattering a particular photon undergoes the longer the integrated path it follows, and the longer the time that elapses before it emerges from of the sample. Some groups have attempted to reduce the deleterious effects of scattering by using pulsed sources and time gating the detection so as to view the sample only in light which has undergone few scatterings. What is measured is a "snapshot" of the sample in light starting at the time of flight for an unscattered beam, and extending long enough in time to obtain sufficient signal for the desired analysis without including much scattered radiation. When the time gate is short, "ballistic" or "snakelike" photons which have undergone no or few scatterings along their path are selected, and shadowgram images similar to those commonly obtained with x-ray's can be obtained.
This approach, however, requires complicated apparatus, and in addition to the intensity limitation from the short time-gate after each pulse of the light source, adds a further limitation on the number of detected photons because the duty-cycle of the pulsed source is low compared to the continuous source of the present invention. Other research groups such as Wist et al., IEEE Transactions on Medical Imaging, 12 (4) 751-757 (1993), have demonstrated that shadowgram-type images can be obtained by severely restricting the angular acceptance range of detected photons about the forward direction, essentially demonstrating that doing so limits the detection to "ballistic" or "snakelike" photons. The Wist et al. apparatus generates a geometrically narrow beam which is raster-scanned across the sample, at a first wavelength, and then generates new images at changed wavelengths. The work of this group, however, also demonstrates a severe limitation on the total flux of transmitted photons which make it inapplicable to the detection of trace constituents in scattering media.
Other workers such as Schmitt et. al., SPIE 1641, 150-161, (1992), have demonstrated advantages for using collimated input and output light on in vitro phantoms that simulate some of the light scattering properties of turbid media, but the transmitted intensity limitation of their system when it was applied to real in vivo measurements made it necessary to change the system design away from this collimated approach. One difficulty appears to be that their in vitro system was designed to "approximate the plane-parallel conditions under which [the theoretical] photon diffusion model was derived," rather than addressing the characteristics of the in vivo sample. Schmitt's collimated system was designed to approximate a "collimated beam of infinite extent" by establishing a finite incident beam of light traversing tissues and confining the collimated detection to a small central region on the exit side, apparently in order to eliminate unwanted edge effects. In addition, the narrowband sources and detector used limited the transmitted intensity.
The failure of Schmitt's design was that insufficient photon flux was available at the detector, so that this system was abandoned for his in vivo work. Instead, Schmitt's in vivo apparatus employed a fiber optic that launched light into the tissue at its large (.about.50 degree) numerical aperture, and an integrating detector on the opposite side of the tissue receiving light through almost the whole hemisphere. Even then, as noted in his article, the system had inadequate light intensity for the measurement he was attempting. His work thus vividly illustrates the light transmission limitations of real tissue that characterizes the prior art.
Thus, it is a specific object of the present invention to balance the light collection efficiency and spatial resolution of the optical sampling system viewing scattering media to simultaneously achieve high detected light intensity and equality of response, as a function of wavelength, to inhomogeneous inclusions within the media. This is accomplished by selecting optical configurations of sources, detectors, and intervening optical elements to minimize the effect of tissue inhomogeneities on the relative changes in signal strengths in each of the different detectors due to the presence of analyte.
It is a further object of the invention to achieve this balance in a way which improves the repeatability of the measurements from site-to-site on a given individual in the presence of disturbances such as motion, breathing, hydration, and the like, with the ultimate objective to achieve universal calibratability of the measurement across subject in the presence of such disturbances.
A related object of the invention is to provide a method of non-invasive concentration measurement in a scattering media which increases the ratio of direct collimated radiation to diffusely scattered radiation reaching the detector, while maintained high integrated light intensity at the detectors.
Another object in the invention is provide an apparatus for non-invasive concentration measurements which maximizes the ratio of direct collimated radiation to diffusely scattered radiation while maintaining high integrated light intensity.
A further object of the invention is to facilitate the use of tighter collimation by increasing the number of photons received in the individual detector resolution elements through broadening their wavelength acceptance range.
A similar objective of the invention is to facilitate the use of tighter collimation by increasing the number of photons received by individual detector resolution elements through increasing their surface area while maintaining their congruency.
Yet another object of the invention is to further facilitate the use of tighter collimation by the use of overlapping broadband detector resolution elements in an analog of human color perception to combine increased photon flux with more efficient separation of similar broad analyte and interferent spectral features.
Consequently, it is a specific object of this invention to select optical configurations of sources, detectors, and intervening optical elements to minimize the effect of tissue inhomogeneities on the relative changes in signal strengths in each of the different detectors due to the presence of analyte.
It is a still further object of this invention to adjust the optical interface to take maximum advantage of the natural spreading characteristics of the light distribution patterns in tissue in maximizing the S/N of the determination.
These and other objects which features the invention will be apparent from the detailed description and the drawing.